Prophylactic hyperthermic intraperitoneal chemotherapy may benefit the long-term survival of patients after radical gastric cancer surgery

Hyperthermic intraperitoneal chemotherapy (HIPEC) has been proven to improve the survival rate of gastric cancer and reduce peritoneal recurrence. We aimed to evaluate the effectiveness and safety of prophylactic HIPEC after radical gastric cancer surgery in this study. Researchers searched for studies published in PubMed, Embase, Web of science, Scopus, Cochrane, Clinical key databases and Microsoft Academic databases to identify studies that examine the impact of prophylactic HIPEC on the survival, recurrence and adverse events of patients undergoing radical gastric cancer surgery. RevMan 5.3 was used to analyze the results and risk of bias. The PROSERO registration number is CRD42021262016. This meta-analysis included 22 studies with a total of 2097 patients, 12 of which are RCTs. The results showed that the 1-, 3- and 5-year overall survival rate was significantly favorable to HIPEC (OR 5.10, 2.07, 1.96 respectively). Compared with the control group, the overall recurrence rate and peritoneal recurrence rate of the HIPEC group were significantly lower (OR 0.41, 0.24 respectively). Significantly favorable to the control group in terms of renal dysfunction and pulmonary dysfunction complications (OR 2.44, 6.03 respectively). Regarding the causes of death due to postoperative recurrence: liver recurrence, lymph node and local recurrence and peritoneal recurrence, the overall effect is not significantly different (OR 0.81, 1.19, 0.37 respectively). 1-, 3- and 5-year overall survival follow-up may be incremented by the prophylactic HIPEC, and which reduce the overall recurrence rate and peritoneal recurrence rate. HIPEC may have high-risk of pulmonary dysfunction and renal dysfunction complications. No difference has been found in the deaths due to recurrence after surgery.

According to the Modified methodological index for non-randomized studies (MINORS) score, we will analyze the data included in the NRCT and complete the quality assessment Table 1. In addition, we extracted the characteristics of the studies and patients and summarized them in Tables 2, 3. The contents are as follows: Author, year of publication, Country, RCT/NRCT, study period, matched factors, ages, gender, and Cy + at the time of diagnosis in Table 2. And the Histologic type, T, N stage, etc. are shown in Table 3. The characteristics of the interventions will be summarized in Table 4. The patients' prognosis and response to treatment are summarized in Table 5.
Outcomes. The primary outcome of this review is the overall survival at 3 years follow-up. The secondary outcomes are the overall survival at 1-and 5-years follow-up; recurrence rate: overall and peritoneal; complication: myelosuppression, leakage, intestinal obstruction, liver dysfunction; deaths due to recurrence after surgery: liver, lymph node and local and peritoneal recurrence. www.nature.com/scientificreports/ Statistical analysis. All the data that needs to be analyzed are dichotomous data, and we choose to report odds ratio (OR). RevMan 5.3 also reported the heterogeneity of the data while producing the forest plot. For heterogeneity test P < 0.05 or I 2 > 50%, we choose random effects model. When the heterogeneity test P > 0.05 or I 2 < 50%, the fixed effects model is often selected. Subgroup analysis is based on the overall heterogeneity inspection results. The fixed effects model is used when the results of heterogeneity between subgroups are consistent, and the random effects model is used when the results of heterogeneity are inconsistent. If the heterogeneity test result I 2 > 80%, we need to perform a sensitivity analysis on the data to exclude studies with significant heterogeneity.

Results
Literature search findings. Two 45). Based on the number of "stars" marked in EndNote X9, we screened clinical studies in the second stage, and 126 studies can be reviewed in full text. After excluding 99 studies, 27 included articles were identified. We evaluated the quality of NRCT among them, three studies with a score of < 12 were excluded [18][19][20][21][22] . This review finally included 22 articles. The literature search findings are represented in PRISMA_2020_flow_diagram (Fig. 1).
Deaths due to recurrence after surgery: lymph node and local recurrence (Fig. 11B). In three studies, 221 patients reported the deaths due to lymph node and local recurrence after surgery [33][34][35] . Analyzing under the fixed effects model, the overall heterogeneity (I 2 = 9%) is not significant. The overall effect is not significantly different (OR 1.19, 95% CI 0.54-2.62).

Discussion
For patients at high risk of peritoneal metastasis, prophylactic HIPEC after radical gastric cancer is a method to reduce peritoneal metastasis and improve the survival rate of patients, but its effect is still controversial. Our study analyzed RCTs and high-quality NRCTs to evaluate the effect of prophylactic HIPEC on long-term survival and safety of patients. This review showed that the prophylactic HIPEC is beneficial to the overall survival rate of patients at 1, 3, and 5 years, and reduces the occurrence of overall and peritoneal metastases. Our results indicate that postoperative pulmonary dysfunction and renal dysfunction are more common in the prophylactic HIPEC group. But it is regrettable that, when we evaluate deaths due to metastatic disease, HIPEC does not have enough advantages. The overall survival rate after gastric cancer resection is a topic of concern. Many studies have reported the long-term survival rate of patients with HIPEC after surgery. Two studies reported that postoperative use of HIPEC for gastric cancer patients with peritoneal metastasis can significantly improve long-term survival 43,45 . With the increase in the incidence of gastric cancer, the effect of prophylactic HIPEC has gradually been paid attention to. In a retrospective study, Liu et al. randomly divided 128 patients into a HIPEC group and a control group. Patients in the HIPEC group received early prophylactic HIPEC + systemic chemotherapy after gastrectomy, and the control group received chemotherapy alone 26 . Through follow-up, the 1, 2, and 5-year overall survival rates of the prophylactic HIPEC group were higher than those of the control group (P < 0.05). Fujimura and his colleagues designed an RCT to evaluate the effect of prophylactic HIPEC on the overall survival rate of patients at 1, 2, and 3 years after surgery 34 . Interestingly, the author set up two experimental groups, CHPP and continuous normothermic peritoneal perfusion (CNPP), and the results reported that the overall survival rates    There are also several studies on the choice of different chemotherapeutic drugs, but due to the small number of studies and differences in doses, the evaluation results are often limited. There is no consensus on drug selection for HIPEC, MMC and platinum drugs are more common in research. The review by Gamboa et al. 49 summarized the choice of HIPEC chemotherapeutic drugs. According to reports, MMC is the first drug used for HIPEC monotherapy, and the most common regimen is 40 mg for 90 min. Cisplatin or oxaliplatin is usually combined with MMC. The common regimen of cisplatin is 50 to 200 mg/m 2 60-90 min, and oxaliplatin has a fast onset, so 460 mg/m 2 for 30-60 min is common. In a PERISCOPE I initial results published in 2020, 460 mg/m 2 oxaliplatin for 30 min with 50 mg/m 2 docetaxel for 90 min is feasible 50 . But this way seems to be more suitable for patients with peritoneal metastases. Macrì et al. 51 considered cisplatin (25 mg/m 2 per liter) + MMC (3.3 mg/m 2 per liter) for 60 min may be more effective. This review conducted a subgroup analysis of three different chemotherapy methods (MMC, cisplatin, MMC + cisplatin), and no matter which method they were, they improved the overall 3-year survival rate of patients. Due to the small number of studies and the differences in dose, duration, temperature, etc., we did not evaluate the effects between groups. In addition, prophylactic or therapeutic laparoscopic HIPEC has been mentioned in multiple studies. In the study of Badgwell et al. 45 53 pointed out that this is usually related to the dose of chemotherapy drugs. Cui et al. 28 designed an RCT to evaluate postoperative myelosuppression. 48 patients were enrolled in the HIPEC group and the control group. Among the patients receiving HIPEC, a total of 27 patients with myelosuppression (Grade I-II: 26, Grade III-IV: 1), and 26 patients in the control group with myelosuppression (Grade I-II: 25, Grade III-IV: 1), there is no significant difference in results. In a study published in 1999, none of the 141 patients in the HIPEC group and the control group had myelosuppression. Our study included 6 literatures to evaluate the occurrence of postoperative myelosuppression, and the results were also without significantly difference. HIPEC's chemotherapy drugs are directly infused into the patient's abdominal cavity, which is different from the conventional intravenous infusion of systemic chemotherapy drugs, so the effect on the whole body may not be obvious. Anastomotic leakage and postoperative intestinal obstruction are considered to be common complications of HIPEC, and the results of this review do not seem to support this view [54][55][56] . Like our results, the incidence of anastomotic leakage in the HIPEC group and the control group in the meta-analysis of Desiderio et al. 46 was not statistically significant (P = 0.63). The study by Sun et al. 48 reported the occurrence of postoperative anastomotic leakage (P = 0.29) and intestinal obstruction (P = 0.77), and the results were also not significantly different, but the number of documents included in the analysis was small. Postoperative organ dysfunction is often reported in patients using HIPEC. In Fan et al. 's 27 study, 36 out of 50 patients developed liver dysfunction, while Zhong et al. 24 evaluated 129 patients and only 1 with postoperative liver dysfunction. In this meta-analysis, we evaluate liver, renal, and pulmonary dysfunction www.nature.com/scientificreports/ after prophylactic HIPEC. The results show that prophylactic HIPEC seems to have a limited effect on liver function, and it is more likely to cause renal dysfunction and lung dysfunction. In a meta-analysis 46 , the risk of renal dysfunction in the HIPEC group was significant (P = 0.01), which is consistent with our results. Another meta-analysis 48 that included 10 RCTs also reported that the HIPEC group had no significant effect on liver function (P = 0.47). In the evaluation results of pulmonary dysfunction in this review, Kunisaki et al. 's 39 research weight is relatively large (40.6%), and there is a certain degree of heterogeneity. In the study of Kunisaki et al., there are significant differences in postoperative pulmonary (73% vs 19%; P < 0.0001) and renal dysfunction (7% vs 0%; P < 0.03). The toxicity of chemotherapeutics has obvious damage to renal function and lung function. Therefore, patients with organ dysfunction should be cautious in choosing HIPEC. Although our study has no statistically significant difference in the overall risk of complications (P = 0.83), this does not mean that the risk of certain complications can be ignored, especially organ dysfunction. HIPEC is regarded as a radical therapy by many studies, therefore, whether to use HIPEC should be discussed considering the patient's situation 19,43,57 . In order to reduce the occurrence of postoperative adverse events, the selection of patients before surgery should be decided through multidisciplinary consultation, and the appropriate treatment plan should be selected according to the principle of individualization 58 . The metastasis of gastric cancer has a significant impact on the survival rate of patients. This review reports the effect of prophylactic HIPEC on the overall metastasis rate and peritoneal metastasis rate, confirming that prophylactic HIPEC reduces the occurrence of gastric cancer metastasis and reduces the risk of death due to peritoneal metastasis. Koemans and his colleagues pointed out in a PERISCOPE I trial that HIPEC can improve the survival rate of patients with gastric cancer, but the control of recurrence rate is not ideal 59 . This is different from our results, which may be due to different inclusion criteria and PERISCOPE I trial. Chia et al. 47 believe that therapeutic HIPEC combined with CRS is not effective for patients with gastric cancer with peritoneal metastasis, while the effect of prophylactic HIPEC is still unclear. As an important method of perioperative chemotherapy, HIPEC is gradually recognized for its role in preventing peritoneal metastasis in advanced gastric carcinoma (AGC) patients 60 . A meta-analysis by Coccolini et al. 61 evaluated the overall metastasis rate and peritoneal metastasis rate of patients after intraperitoneal chemotherapy (IP). A total of 8 studies were included in the overall metastasis group, and 9 studies were included in the peritoneal metastasis group. Coccolini and his colleagues reported that IP improved the overall metastasis rate of patients, and prophylactic IP significantly reduced the occurrence of peritoneal metastases. This is consistent with the results of this review. An expert consensus published in 2019 pointed out that the peritoneal metastasis of some cancers should not be regarded as end-stage disease, but localized spread 51 . This suggests that the prevention of gastric cancer peritoneal metastasis should follow the principle of local treatment under the premise of systemic treatment. At the same time, the rise of immunotherapy also provides new ideas for the treatment of gastric cancer. Catumaxomab is currently in Phase III clinical trials in China, mainly for AGC patients with peritoneal metastasis. In the future, the treatment Figure 11. Death due to recurrence after surgery: liver recurrence (A), Death due to recurrence after surgery: lymph node and local recurrence (B), Death due to recurrence after surgery: peritoneum recurrence (C).

Scientific Reports
| (2022) 12:2583 | https://doi.org/10.1038/s41598-022-06417-y www.nature.com/scientificreports/ of gastric cancer will be more individualized, so the correct evaluation of patients' treatment methods will be an important part of tumor treatment 49 . Based on the existing evidence, we can basically affirm that preventive HIPEC can reduce the incidence of patients with peritoneal metastasis and the number of deaths due to peritoneal metastasis, but a large sample is still needed, and high-quality RCTs further evaluate the safety and the role of inhibiting disease progression of prophylactic HIPEC for patients. This systematic review and meta-analysis contain some limitations. First, we included 10 NRCTs. Although they passed the quality assessment, this may affect the accuracy of the results. Second, China and Japan are two countries with a high incidence of gastric cancer, so there are more HIPEC-related clinical studies published 50 . We searched 3 Japanese literatures, but none of them were available. Two investigators searched the Chinese national knowledge infrastructure (CNKI) database, and we did not include them because the studies did not meet the inclusion criteria of this review or did not pass the quality assessment. In addition, there is a certain degree of heterogeneity in our research. For example, differences in patient characteristics, countries, medical levels, treatment plans, chemotherapy drugs, etc. may affect the credibility of the results.